The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists.
CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
Piperidine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer""s disease are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 5,952,349; and 5,977,138.
Piperidine and piperazine derivatives useful in the treatment of AIDS are disclosed in WO 00/66559 and WO 00/66558.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9: 187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The present invention relates to compounds useful as CCR5 antagonist represented by the structural formula I 
or a pharmaceutically acceptable salt or isomer thereof, wherein:
Q, X and Z are independently selected from the group consisting of CH and N, provided that one or both of Q and Z is N;
R, R4, R5, R6 and R7 are independently selected from the group consisting of H and (C1-C6)alkyl;
R1 is H, (C1-C6)alkyl, fluoro-(C1-C6)alkyl-, R9-aryl(C1-C6)alkyl-, R9-heteroaryl-(C1-C6)alkyl-, (C1-C6)alkyl-SO2xe2x80x94, (C3-C6)cycloalkyl-SO2xe2x80x94, fluoro-(C1-C6)alkyl-SO2xe2x80x94, R9-aryl-SO2xe2x80x94, R9-heteroaryl-SO2xe2x80x94, N(R22)(R23)xe2x80x94SO2xe2x80x94, (C1-C6)alkyl-C(O)xe2x80x94, (C3-C6)cyclo-alkyl-C(O)xe2x80x94, fluoro-(C1-C6)alkyl-C(O)xe2x80x94, R9-aryl-C(O)xe2x80x94, NHxe2x80x94(C1-C6)alkyl-C(O)xe2x80x94 or R9-aryl-NHxe2x80x94C(O)xe2x80x94;
R2 is H or (C1-C6)alkyl, and R3 is H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-, (C3-C10)-cycloalkyl-, (C3-C10)cycloalkyl(C1-6)alkyl-, R9-aryl, R9-aryl(C1 -C6)-alkyl-, R9-heteroaryl, or R9-heteroaryl(C1-C6)alkyl-, provided that both X and Z are not each N;
or R2 and R3 together are xe2x95x90O, xe2x95x90NOR10, xe2x95x90Nxe2x80x94NR11R12 or xe2x95x90CH(C1-C6)alkyl, provided that when one or both of X and Z is N, R2 and R3 together are not xe2x95x90CH(C1-C6)alkyl;
and when X and Z are each CH, R3 can also be (C1-C6)alkoxy, R9-aryloxy, R9-heteroaryloxy, (C1-C6)alkyl-C(O)Oxe2x80x94, (C1-C6)alkyl-NHxe2x80x94C(O)Oxe2x80x94, N((C1-C6)alkyl)2xe2x80x94C(O)Oxe2x80x94, (C1-C6)alkyl-C(O)xe2x80x94NR13xe2x80x94, (C1-C6)alkyl-Oxe2x80x94C(O)xe2x80x94NR13xe2x80x94, (C1-C6)alkyl-NHxe2x80x94C(O)xe2x80x94NR13xe2x80x94, or N((C1-C6)alkyl)2xe2x80x94C(O)xe2x80x94NR13xe2x80x94;
R8 is (R14,R15,R16)-substituted phenyl, (R14,R15,R16)-substituted 6-membered heteroaryl, (R14,R15,R16)-substituted 6-membered heteroaryl N-oxide, (R17,R18)-substituted 5-membered heteroaryl, naphthyl, fluorenyl, diphenylmethyl, 
R9 is 1, 2 or 3 substituents independently selected from the group consisting of H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, xe2x80x94CF3, xe2x80x94OCF3, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94 and xe2x80x94N(R22)(R23);
R10 is H, (C1-C6)alkyl, fluoro(C1-C6)alkyl-, (C3-C10)cycloalkyl(C1-C6)alkyl-, hydroxy(C2-C6)alkyl-, (C1-C6)alkyl-Oxe2x80x94(C2-C6)alkyl-, (C1-C6)alkyl-Oxe2x80x94C(O)xe2x80x94(C1-C6)alkyl- or N(R22)(R23)xe2x80x94C(O)xe2x80x94(C1-C6)alkyl-;
R11 and R12 are independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C10)cycloalkyl, or R11and R12 together are C2-C6 alkylene and form a ring with the nitrogen to which they are attached;
R14 and R15 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR22R23, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl and xe2x80x94OCF3;
R16 is R14, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR24, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R24)CONR25R26, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C10)cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N(R22)(R23), xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2xe2x80x94(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR27, xe2x80x94SOR27, xe2x80x94SO2R27, xe2x80x94SO2NH(R22), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl-, xe2x80x94CON R24R25, xe2x80x94CON(CH2CH2OCH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R24, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R17 is (C1-C6)alkyl, xe2x80x94N(R22)(R23) or R19-phenyl;
R13, R18, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H and (C1-C6)alkyl;
R19 is 1, 2 or 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, xe2x80x94CF3, xe2x80x94CO2R25, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R20 and R21 are independently selected from the group consisting of H and (C1-C6)alkyl, or R20 and R21 together with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; and
R27 is (C1-C6)alkyl or phenyl.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of at least one compound of formula I in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of at least one compound of formula I in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of at least one compound of formula I. Another aspect of the invention is a method of treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a human in need of such treatment an effective amount of at least one compound of formula I. Also contemplated is the use of at least one compound of formula I for the preparation of a medicament for the treatment of HIV, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
Still another aspect of this invention is the use of at least one compound of formula I of this invention in combination with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus for the treatment of AIDS. Still another aspect of this invention is the use of at least one compound of formula I of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The compound(s) of formula I and antiviral or other agents which are components of the combination can be administered in a single dosage form or they can be administered separately. Therefore, a pharmaceutical composition comprising at least one compound of formula I and one or more antiviral or other agents useful in the treatment of HIV is comtemplated, as well as a pharmaceutical composition comprising at least one compound of formula I and one or more antiviral or other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis; a kit comprising separate dosage forms of the actives for treating HIV, solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis is also contemplated.